EA030586B1 - Интермедиат для получения антагонистов рецептора нейрокинина-3 - Google Patents
Интермедиат для получения антагонистов рецептора нейрокинина-3 Download PDFInfo
- Publication number
- EA030586B1 EA030586B1 EA201591204A EA201591204A EA030586B1 EA 030586 B1 EA030586 B1 EA 030586B1 EA 201591204 A EA201591204 A EA 201591204A EA 201591204 A EA201591204 A EA 201591204A EA 030586 B1 EA030586 B1 EA 030586B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- triazolo
- methyl
- tetrahydro
- pyrazin
- mmol
- Prior art date
Links
- 239000002740 neurokinin 3 receptor antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- -1 2,4-dimethoxybenzyl Chemical group 0.000 claims abstract description 94
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 239000012453 solvate Substances 0.000 claims abstract description 20
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims abstract description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 192
- 230000015572 biosynthetic process Effects 0.000 description 101
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- 238000003786 synthesis reaction Methods 0.000 description 95
- 239000000543 intermediate Substances 0.000 description 91
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 88
- 238000000034 method Methods 0.000 description 81
- 238000007429 general method Methods 0.000 description 65
- 230000014759 maintenance of location Effects 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 51
- 239000000243 solution Substances 0.000 description 49
- 239000011541 reaction mixture Substances 0.000 description 45
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000003153 chemical reaction reagent Substances 0.000 description 39
- 239000000047 product Substances 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000004296 chiral HPLC Methods 0.000 description 28
- LWRSYTXEQUUTKW-UHFFFAOYSA-N DMB Natural products COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
- 239000003480 eluent Substances 0.000 description 24
- 239000002904 solvent Substances 0.000 description 23
- 108010040716 Neurokinin-3 Receptors Proteins 0.000 description 22
- 102000002003 Neurokinin-3 Receptors Human genes 0.000 description 22
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 125000000217 alkyl group Chemical group 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 125000003118 aryl group Chemical group 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 18
- 125000001072 heteroaryl group Chemical group 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical class O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 239000002253 acid Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 229910052736 halogen Inorganic materials 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- GAVMRTMJEVMRGR-UHFFFAOYSA-N 2,3,5,6-tetrahydro-1h-triazolo[4,5-b]pyrazine Chemical class N1CCNC2=C1N=NN2 GAVMRTMJEVMRGR-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 125000000753 cycloalkyl group Chemical group 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- ONAWFUIPKRAZKL-UHFFFAOYSA-N 2-methyl-1,3-thiazole-4-carbohydrazide Chemical compound CC1=NC(C(=O)NN)=CS1 ONAWFUIPKRAZKL-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 210000003169 central nervous system Anatomy 0.000 description 10
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000012047 saturated solution Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000005755 formation reaction Methods 0.000 description 9
- 125000001188 haloalkyl group Chemical group 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 230000005855 radiation Effects 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 229910002651 NO3 Inorganic materials 0.000 description 8
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
- 229910019142 PO4 Inorganic materials 0.000 description 8
- 238000000441 X-ray spectroscopy Methods 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000006210 cyclodehydration reaction Methods 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 8
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- 230000006340 racemization Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 102000046798 Neurokinin B Human genes 0.000 description 7
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 7
- 101800002813 Neurokinin-B Proteins 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 229960004592 isopropanol Drugs 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 6
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 description 5
- JPVUWCPKMYXOKW-UHFFFAOYSA-N 4-phenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=C1 JPVUWCPKMYXOKW-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 102100024304 Protachykinin-1 Human genes 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000000825 ultraviolet detection Methods 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- CRBZVDLXAIFERF-UHFFFAOYSA-N 2,4,6-trimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C(OC)=C1 CRBZVDLXAIFERF-UHFFFAOYSA-N 0.000 description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 4
- YTAOGRZEXHXXFD-UHFFFAOYSA-N 8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound CC1NCCN2C1=NN=C2C1=CC=CC(C)=N1 YTAOGRZEXHXXFD-UHFFFAOYSA-N 0.000 description 4
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 4
- 102000009151 Luteinizing Hormone Human genes 0.000 description 4
- 108010073521 Luteinizing Hormone Proteins 0.000 description 4
- 108010040722 Neurokinin-2 Receptors Proteins 0.000 description 4
- 239000004677 Nylon Substances 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 4
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 4
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000010354 integration Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229940040129 luteinizing hormone Drugs 0.000 description 4
- 229920001778 nylon Polymers 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 201000000980 schizophrenia Diseases 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 229910052726 zirconium Inorganic materials 0.000 description 4
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 3
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 3
- UQIRXNLWDMURMI-UHFFFAOYSA-N 2-ethyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound S1C(CC)=NC(C=2N3CCNC(C)C3=NN=2)=C1 UQIRXNLWDMURMI-UHFFFAOYSA-N 0.000 description 3
- RJKLKVDFRCSQNB-UHFFFAOYSA-N 2-methyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole;hydrochloride Chemical compound Cl.S1C(C)=NC(C=2N3CCNCC3=NN=2)=C1 RJKLKVDFRCSQNB-UHFFFAOYSA-N 0.000 description 3
- BSPUWRUTIOUGMZ-UHFFFAOYSA-N 3-methylpiperazin-2-one Chemical compound CC1NCCNC1=O BSPUWRUTIOUGMZ-UHFFFAOYSA-N 0.000 description 3
- WVNRXYGQXBXMGC-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-6-ethoxy-5-methyl-3,5-dihydro-2h-pyrazine Chemical compound CC1C(OCC)=NCCN1CC1=CC=C(OC)C=C1OC WVNRXYGQXBXMGC-UHFFFAOYSA-N 0.000 description 3
- AKIBBMUXIUBRAY-UHFFFAOYSA-N 4-methyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound CC1NCCN2C1=NN=C2C1=NC(C)=CS1 AKIBBMUXIUBRAY-UHFFFAOYSA-N 0.000 description 3
- WWIBCNCKODGBTI-UHFFFAOYSA-N 4-thiophen-2-ylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CS1 WWIBCNCKODGBTI-UHFFFAOYSA-N 0.000 description 3
- RNVLWLLEQBBBMM-UHFFFAOYSA-N 6-methylpyridine-2-carbohydrazide Chemical compound CC1=CC=CC(C(=O)NN)=N1 RNVLWLLEQBBBMM-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 101800000399 Neurokinin A Proteins 0.000 description 3
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 3
- 102400000097 Neurokinin A Human genes 0.000 description 3
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 3
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 3
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 3
- 101800003906 Substance P Proteins 0.000 description 3
- 102000007124 Tachykinin Receptors Human genes 0.000 description 3
- 108010072901 Tachykinin Receptors Proteins 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 210000003295 arcuate nucleus Anatomy 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000005242 carbamoyl alkyl group Chemical group 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 3
- 206010007776 catatonia Diseases 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 229960002510 mandelic acid Drugs 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- XRJYMHASJFSHRH-UHFFFAOYSA-N 1-ethyl-2,4-dimethoxybenzene Chemical compound CCC1=CC=C(OC)C=C1OC XRJYMHASJFSHRH-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- OBSLLHNATPQFMJ-UHFFFAOYSA-N 2,4-Dimethylthiazole Chemical compound CC1=CSC(C)=N1 OBSLLHNATPQFMJ-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- SZYROWDCAVLZLC-UHFFFAOYSA-N 2-[7-[(4-methoxyphenyl)methyl]-8-methyl-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-4-methyl-1,3-thiazole Chemical compound C1=CC(OC)=CC=C1CN1C(C)C2=NN=C(C=3SC=C(C)N=3)N2CC1 SZYROWDCAVLZLC-UHFFFAOYSA-N 0.000 description 2
- SSEFLABLGALODF-UHFFFAOYSA-N 2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole;hydrochloride Chemical compound Cl.CC1NCCN2C1=NN=C2C1=CSC(C)=N1 SSEFLABLGALODF-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- JIDAHYHCQJXNTD-UHFFFAOYSA-N 4-(hydrazinecarbonyl)benzenesulfonamide Chemical compound NNC(=O)C1=CC=C(S(N)(=O)=O)C=C1 JIDAHYHCQJXNTD-UHFFFAOYSA-N 0.000 description 2
- VRRFLEAHVFVBIE-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazin-2-one Chemical compound COC1=CC(OC)=CC=C1CN1C(C)C(=O)NCC1 VRRFLEAHVFVBIE-UHFFFAOYSA-N 0.000 description 2
- YXTHSLRQYKQGPO-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methyl]-3-methylpiperazin-2-one Chemical compound C1=CC(OC)=CC=C1CN1C(C)C(=O)NCC1 YXTHSLRQYKQGPO-UHFFFAOYSA-N 0.000 description 2
- INJNWSGIEOQVBL-GFCCVEGCSA-N 4-[(8r)-7-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-2-methyl-1,3-thiazole Chemical compound COC1=CC(OC)=CC=C1CN1[C@H](C)C2=NN=C(C=3N=C(C)SC=3)N2CC1 INJNWSGIEOQVBL-GFCCVEGCSA-N 0.000 description 2
- KRXWBFGOEMMEMO-UHFFFAOYSA-N 4-methyl-1,3-thiazole-2-carbohydrazide Chemical compound CC1=CSC(C(=O)NN)=N1 KRXWBFGOEMMEMO-UHFFFAOYSA-N 0.000 description 2
- UECDQUOWFRTJOH-UHFFFAOYSA-N 4-thiophen-2-ylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CS1 UECDQUOWFRTJOH-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 206010012239 Delusion Diseases 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 102000006771 Gonadotropins Human genes 0.000 description 2
- 108010086677 Gonadotropins Proteins 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 101000587820 Homo sapiens Selenide, water dikinase 1 Proteins 0.000 description 2
- 101000701815 Homo sapiens Spermidine synthase Proteins 0.000 description 2
- 206010021703 Indifference Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000013599 Kisspeptins Human genes 0.000 description 2
- 108010012048 Kisspeptins Proteins 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 102100030413 Spermidine synthase Human genes 0.000 description 2
- 102100037342 Substance-K receptor Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010549 co-Evaporation Methods 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 231100000868 delusion Toxicity 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 230000002996 emotional effect Effects 0.000 description 2
- 239000006274 endogenous ligand Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000002622 gonadotropin Substances 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 2
- 238000010829 isocratic elution Methods 0.000 description 2
- KAHDONZOCXSKII-NJVVDGNHSA-N kisspeptin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)O)C1=CN=CN1 KAHDONZOCXSKII-NJVVDGNHSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- PUGKVZUKRPVFBP-UHFFFAOYSA-N methyl 4,5-dimethyl-1,3-thiazole-2-carboxylate Chemical compound COC(=O)C1=NC(C)=C(C)S1 PUGKVZUKRPVFBP-UHFFFAOYSA-N 0.000 description 2
- CYWIZMOZBTXFIL-UHFFFAOYSA-N methyl 6-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(C)=N1 CYWIZMOZBTXFIL-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VQXLQBCWWLKVDP-UHFFFAOYSA-N tert-butyl 6-ethoxy-5-methyl-3,5-dihydro-2h-pyrazine-4-carboxylate Chemical compound CCOC1=NCCN(C(=O)OC(C)(C)C)C1C VQXLQBCWWLKVDP-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 238000002849 thermal shift Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- VRRFLEAHVFVBIE-SNVBAGLBSA-N (3r)-4-[(2,4-dimethoxyphenyl)methyl]-3-methylpiperazin-2-one Chemical compound COC1=CC(OC)=CC=C1CN1[C@H](C)C(=O)NCC1 VRRFLEAHVFVBIE-SNVBAGLBSA-N 0.000 description 1
- YTAOGRZEXHXXFD-SECBINFHSA-N (8r)-8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound N([C@@H]1C)CCN2C1=NN=C2C1=CC=CC(C)=N1 YTAOGRZEXHXXFD-SECBINFHSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- 125000006083 1-bromoethyl group Chemical group 0.000 description 1
- UVGCGIWXPOPLOO-UHFFFAOYSA-N 2,5-dimethyl-1,3-thiazole-4-carbohydrazide Chemical compound CC1=NC(C(=O)NN)=C(C)S1 UVGCGIWXPOPLOO-UHFFFAOYSA-N 0.000 description 1
- MULLGEOWBPZFMW-UHFFFAOYSA-N 2,5-dimethyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound CC1NCCN2C1=NN=C2C=1N=C(C)SC=1C MULLGEOWBPZFMW-UHFFFAOYSA-N 0.000 description 1
- IBFCYQLKWZRFKA-UHFFFAOYSA-N 2-(trifluoromethyl)-1,3-thiazole-4-carbohydrazide Chemical compound NNC(=O)C1=CSC(C(F)(F)F)=N1 IBFCYQLKWZRFKA-UHFFFAOYSA-N 0.000 description 1
- FOSUXIWGJXCQDZ-UHFFFAOYSA-N 2-cyclopropyl-1,3-oxazole-4-carbohydrazide Chemical compound NNC(=O)C1=COC(C2CC2)=N1 FOSUXIWGJXCQDZ-UHFFFAOYSA-N 0.000 description 1
- NZOCQYSHVMPNQK-UHFFFAOYSA-N 2-cyclopropyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-oxazole Chemical compound CC1NCCN2C1=NN=C2C(N=1)=COC=1C1CC1 NZOCQYSHVMPNQK-UHFFFAOYSA-N 0.000 description 1
- GKZBWHYPQQOIRD-UHFFFAOYSA-N 2-ethenyl-1,3-thiazole-4-carbohydrazide Chemical compound NNC(=O)C1=CSC(C=C)=N1 GKZBWHYPQQOIRD-UHFFFAOYSA-N 0.000 description 1
- UGMCHNUYVFTRNY-UHFFFAOYSA-N 2-ethenyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound S1C(C=C)=NC(C=2N3CCNCC3=NN=2)=C1 UGMCHNUYVFTRNY-UHFFFAOYSA-N 0.000 description 1
- YDTVSMRIPUZMOB-UHFFFAOYSA-N 2-ethenyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound CC1NCCN2C1=NN=C2C1=CSC(C=C)=N1 YDTVSMRIPUZMOB-UHFFFAOYSA-N 0.000 description 1
- SWTJVOQINYIXDZ-UHFFFAOYSA-N 2-ethyl-1,3-thiazole-4-carbohydrazide Chemical compound CCC1=NC(C(=O)NN)=CS1 SWTJVOQINYIXDZ-UHFFFAOYSA-N 0.000 description 1
- GBQAWWYOPRFGMG-UHFFFAOYSA-N 2-methyl-1,3-oxazole-4-carbohydrazide Chemical compound CC1=NC(C(=O)NN)=CO1 GBQAWWYOPRFGMG-UHFFFAOYSA-N 0.000 description 1
- IRNCEWKQHJBUKN-UHFFFAOYSA-N 2-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-oxazole Chemical compound CC1NCCN2C1=NN=C2C1=COC(C)=N1 IRNCEWKQHJBUKN-UHFFFAOYSA-N 0.000 description 1
- UBCSWRFWSMHMGZ-LURJTMIESA-N 2-methyl-4-[(8s)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-1,3-thiazole Chemical compound N([C@H]1C)CCN2C1=NN=C2C1=CSC(C)=N1 UBCSWRFWSMHMGZ-LURJTMIESA-N 0.000 description 1
- GUGQQGROXHPINL-UHFFFAOYSA-N 2-oxobutanoyl chloride Chemical compound CCC(=O)C(Cl)=O GUGQQGROXHPINL-UHFFFAOYSA-N 0.000 description 1
- HLLSRGCDOXIZMO-UHFFFAOYSA-N 2-propan-2-yl-1,3-thiazole-4-carbohydrazide Chemical compound CC(C)C1=NC(C(=O)NN)=CS1 HLLSRGCDOXIZMO-UHFFFAOYSA-N 0.000 description 1
- JFUCJKTZZPIAGH-UHFFFAOYSA-N 2-propan-2-yl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-oxazole;hydrochloride Chemical compound Cl.O1C(C(C)C)=NC(C=2N3CCNCC3=NN=2)=C1 JFUCJKTZZPIAGH-UHFFFAOYSA-N 0.000 description 1
- MAVZRZVARYSYLR-UHFFFAOYSA-N 2-propan-2-yl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole;hydrochloride Chemical compound Cl.S1C(C(C)C)=NC(C=2N3CCNCC3=NN=2)=C1 MAVZRZVARYSYLR-UHFFFAOYSA-N 0.000 description 1
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- NJXIVZSIOKHBNP-UHFFFAOYSA-N 3-(6-bromopyridin-2-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;dihydrochloride Chemical compound Cl.Cl.CC1NCCN2C1=NN=C2C1=CC=CC(Br)=N1 NJXIVZSIOKHBNP-UHFFFAOYSA-N 0.000 description 1
- QBHWZTHKHVEAIB-UHFFFAOYSA-N 3-methyl-1,2,4-oxadiazole-5-carbohydrazide Chemical compound CC1=NOC(C(=O)NN)=N1 QBHWZTHKHVEAIB-UHFFFAOYSA-N 0.000 description 1
- UJQISHJANPSPTN-UHFFFAOYSA-N 3-methyl-1,2,4-thiadiazole-5-carbohydrazide Chemical compound CC1=NSC(C(=O)NN)=N1 UJQISHJANPSPTN-UHFFFAOYSA-N 0.000 description 1
- DQOQDKYYQXYIPJ-UHFFFAOYSA-N 3-methyl-4-[(2,4,6-trimethoxyphenyl)methyl]piperazin-2-one Chemical compound COC1=CC(OC)=CC(OC)=C1CN1C(C)C(=O)NCC1 DQOQDKYYQXYIPJ-UHFFFAOYSA-N 0.000 description 1
- AWQZIJVUIUPEEK-UHFFFAOYSA-N 3-methyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole;hydrochloride Chemical compound Cl.CC1NCCN2C1=NN=C2C1=NC(C)=NO1 AWQZIJVUIUPEEK-UHFFFAOYSA-N 0.000 description 1
- GNEWLTDOXNCFAI-UHFFFAOYSA-N 3-methyl-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole;hydrochloride Chemical compound Cl.CC1NCCN2C1=NN=C2C1=NC(C)=NS1 GNEWLTDOXNCFAI-UHFFFAOYSA-N 0.000 description 1
- KRLPXYYIPOXGLM-UHFFFAOYSA-N 3-propan-2-yl-1,2,4-thiadiazole-5-carbohydrazide Chemical compound CC(C)C1=NSC(C(=O)NN)=N1 KRLPXYYIPOXGLM-UHFFFAOYSA-N 0.000 description 1
- OGTFPTGXBLUEDW-UHFFFAOYSA-N 4,5-dimethyl-1,3-thiazole-2-carbohydrazide Chemical compound CC=1N=C(C(=O)NN)SC=1C OGTFPTGXBLUEDW-UHFFFAOYSA-N 0.000 description 1
- ICWKPMXHMDXUNE-UHFFFAOYSA-N 4,5-dimethyl-1,3-thiazole-2-carboxylic acid Chemical compound CC=1N=C(C(O)=O)SC=1C ICWKPMXHMDXUNE-UHFFFAOYSA-N 0.000 description 1
- VPJQPGQJBOKSBQ-UHFFFAOYSA-N 4,5-dimethyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound CC1NCCN2C1=NN=C2C1=NC(C)=C(C)S1 VPJQPGQJBOKSBQ-UHFFFAOYSA-N 0.000 description 1
- VCAYDDXTOXXOQN-UHFFFAOYSA-N 4,5-dimethyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole hydrochloride Chemical compound Cl.CC1NCCN2C1=NN=C2C1=NC(C)=C(C)S1 VCAYDDXTOXXOQN-UHFFFAOYSA-N 0.000 description 1
- JMOOIUJUQROTRP-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(trifluoromethyl)-1,3-thiazole;hydrochloride Chemical compound Cl.S1C(C(F)(F)F)=NC(C=2N3CCNCC3=NN=2)=C1 JMOOIUJUQROTRP-UHFFFAOYSA-N 0.000 description 1
- GKTQVNSZPATZNL-UHFFFAOYSA-N 4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazol-2-amine Chemical compound CC1NCCN2C1=NN=C2C1=CSC(N)=N1 GKTQVNSZPATZNL-UHFFFAOYSA-N 0.000 description 1
- PUMREIFKTMLCAF-UHFFFAOYSA-N 4-methyl-1,3-oxazole Chemical compound CC1=COC=N1 PUMREIFKTMLCAF-UHFFFAOYSA-N 0.000 description 1
- NEDGXOJJEBKHIA-UHFFFAOYSA-N 4-methyl-1,3-oxazole-2-carbohydrazide Chemical compound CC1=COC(C(=O)NN)=N1 NEDGXOJJEBKHIA-UHFFFAOYSA-N 0.000 description 1
- GNGDWDFLILPTKL-UHFFFAOYSA-N 4-methyl-1,3-thiazole-2-carboxylic acid Chemical compound CC1=CSC(C(O)=O)=N1 GNGDWDFLILPTKL-UHFFFAOYSA-N 0.000 description 1
- VSWDKJRPEMSPPA-UHFFFAOYSA-N 4-methyl-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-thiazole Chemical compound CC1=CSC(C=2N3CCNCC3=NN=2)=N1 VSWDKJRPEMSPPA-UHFFFAOYSA-N 0.000 description 1
- CRMIMNWHBWXIRB-UHFFFAOYSA-N 4-methyl-2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,3-oxazole;hydrochloride Chemical compound Cl.CC1NCCN2C1=NN=C2C1=NC(C)=CO1 CRMIMNWHBWXIRB-UHFFFAOYSA-N 0.000 description 1
- HTKIIWXQTFWSSX-UHFFFAOYSA-N 5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-propan-2-yl-1,2,4-thiadiazole;hydrochloride Chemical compound Cl.CC(C)C1=NSC(C=2N3CCNC(C)C3=NN=2)=N1 HTKIIWXQTFWSSX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- DCRDZICLFLDBFN-UHFFFAOYSA-N 5-phenyl-n-pyrazin-2-yl-1,3-thiazol-2-amine Chemical compound C=1N=CC=NC=1NC(S1)=NC=C1C1=CC=CC=C1 DCRDZICLFLDBFN-UHFFFAOYSA-N 0.000 description 1
- YYEUYAHLSYOWKV-UHFFFAOYSA-N 6-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1h-pyridin-2-one Chemical compound CC1NCCN2C1=NN=C2C1=CC=CC(=O)N1 YYEUYAHLSYOWKV-UHFFFAOYSA-N 0.000 description 1
- VRCWSYYXUCKEED-UHFFFAOYSA-N 6-Hydroxypicolinic acid Chemical compound OC(=O)C1=CC=CC(=O)N1 VRCWSYYXUCKEED-UHFFFAOYSA-N 0.000 description 1
- KFPXUSSGMOEMEJ-UHFFFAOYSA-N 6-[8-methyl-7-(4-thiophen-2-ylbenzoyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]pyridine-2-carbonitrile Chemical compound CC1N(C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)CCN2C1=NN=C2C1=CC=CC(C#N)=N1 KFPXUSSGMOEMEJ-UHFFFAOYSA-N 0.000 description 1
- XURXQNUIGWHWHU-UHFFFAOYSA-N 6-bromopyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC(Br)=N1 XURXQNUIGWHWHU-UHFFFAOYSA-N 0.000 description 1
- XJSVIFOTYIIGLM-UHFFFAOYSA-N 6-ethoxy-4-[(4-methoxyphenyl)methyl]-5-methyl-3,5-dihydro-2h-pyrazine Chemical compound CC1C(OCC)=NCCN1CC1=CC=C(OC)C=C1 XJSVIFOTYIIGLM-UHFFFAOYSA-N 0.000 description 1
- LTUUGSGSUZRPRV-UHFFFAOYSA-N 6-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CC(C(O)=O)=N1 LTUUGSGSUZRPRV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- MFJBXHDWECAUII-UHFFFAOYSA-N 8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;dihydrochloride Chemical compound Cl.Cl.CC1NCCN2C1=NN=C2C1=CC=CC(C)=N1 MFJBXHDWECAUII-UHFFFAOYSA-N 0.000 description 1
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000007415 Anhedonia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 208000001495 Disorganized Schizophrenia Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241001302806 Helogenes Species 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 1
- 101000655188 Homo sapiens Tachykinin-3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 150000007945 N-acyl ureas Chemical class 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000019299 Neurokinin NK3 receptors Human genes 0.000 description 1
- 108050006653 Neurokinin NK3 receptors Proteins 0.000 description 1
- 102000009493 Neurokinin receptors Human genes 0.000 description 1
- 108050000302 Neurokinin receptors Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- 208000036753 Schizophrenia, disorganised type Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 102100033009 Tachykinin-3 Human genes 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- DMKOUSMRHGWAAC-CQSZACIVSA-N [(8r)-3-(2-ethyl-1,3-thiazol-4-yl)-8-methyl-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone Chemical compound S1C(CC)=NC(C=2N3CCN([C@H](C)C3=NN=2)C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)=C1 DMKOUSMRHGWAAC-CQSZACIVSA-N 0.000 description 1
- DMKOUSMRHGWAAC-UHFFFAOYSA-N [3-(2-ethyl-1,3-thiazol-4-yl)-8-methyl-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone Chemical compound S1C(CC)=NC(C=2N3CCN(C(C)C3=NN=2)C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)=C1 DMKOUSMRHGWAAC-UHFFFAOYSA-N 0.000 description 1
- WDIRZJJVUSDZRM-UHFFFAOYSA-N [3-(6-bromopyridin-2-yl)-8-methyl-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone Chemical compound CC1N(C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)CCN2C1=NN=C2C1=CC=CC(Br)=N1 WDIRZJJVUSDZRM-UHFFFAOYSA-N 0.000 description 1
- WZHKQWSHHGMARO-UHFFFAOYSA-N [8-methyl-3-(4-methyl-1,3-thiazol-2-yl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-(4-thiophen-2-ylphenyl)methanone Chemical compound CC1N(C(=O)C=2C=CC(=CC=2)C=2SC=CC=2)CCN2C1=NN=C2C1=NC(C)=CS1 WZHKQWSHHGMARO-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005153 alkyl sulfamoyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000037020 contractile activity Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WABIKPGZJAHEHK-UHFFFAOYSA-N cyclohexa-1,3-dien-1-ylbenzene Chemical compound C1=CCCC(C=2C=CC=CC=2)=C1 WABIKPGZJAHEHK-UHFFFAOYSA-N 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- KYSDUPXCQVHOMY-UHFFFAOYSA-N ethyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)C1=CSC(CCN)=N1 KYSDUPXCQVHOMY-UHFFFAOYSA-N 0.000 description 1
- CSKBQHOSNPFIQC-UHFFFAOYSA-N ethyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(NC(=O)OC(C)(C)C)=N1 CSKBQHOSNPFIQC-UHFFFAOYSA-N 0.000 description 1
- QWWPUBQHZFHZSF-UHFFFAOYSA-N ethyl 2-methyl-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)C1=CSC(C)=N1 QWWPUBQHZFHZSF-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- YPNCRQZLESKCGY-UHFFFAOYSA-N ethyl 3-methyl-1,2,4-oxadiazole-5-carboxylate Chemical compound CCOC(=O)C1=NC(C)=NO1 YPNCRQZLESKCGY-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical class OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- SWQYWYUMRAIOJA-UHFFFAOYSA-N methyl 3-methyl-1,2,4-thiadiazole-5-carboxylate Chemical compound COC(=O)C1=NC(C)=NS1 SWQYWYUMRAIOJA-UHFFFAOYSA-N 0.000 description 1
- FCWRXXDUOZLDMA-UHFFFAOYSA-N methyl 3-propan-2-yl-1,2,4-thiadiazole-5-carboxylate Chemical compound COC(=O)C1=NC(C(C)C)=NS1 FCWRXXDUOZLDMA-UHFFFAOYSA-N 0.000 description 1
- DFFKHMIAXOVACS-UHFFFAOYSA-N methyl 4-methyl-1,3-oxazole-2-carboxylate Chemical compound COC(=O)C1=NC(C)=CO1 DFFKHMIAXOVACS-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006256 n-propyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC(*)=O 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000024715 positive regulation of secretion Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000000698 schizophrenic effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- FVZDKQPGHDCJKM-UHFFFAOYSA-N tert-butyl 1,2,5,6-tetrahydrotriazolo[4,5-b]pyrazine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC2=C1N=NN2 FVZDKQPGHDCJKM-UHFFFAOYSA-N 0.000 description 1
- KKVKQTLLEBWZTR-UHFFFAOYSA-N tert-butyl 2-methyl-3-oxopiperazine-1-carboxylate Chemical compound CC1N(C(=O)OC(C)(C)C)CCNC1=O KKVKQTLLEBWZTR-UHFFFAOYSA-N 0.000 description 1
- UQMQQKRBHXXPMA-UHFFFAOYSA-N tert-butyl 6-ethoxy-3,5-dihydro-2h-pyrazine-4-carboxylate Chemical compound CCOC1=NCCN(C(=O)OC(C)(C)C)C1 UQMQQKRBHXXPMA-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical group CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Psychiatry (AREA)
- Hematology (AREA)
- Gynecology & Obstetrics (AREA)
- Obesity (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Child & Adolescent Psychology (AREA)
- Pregnancy & Childbirth (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11183678 | 2011-10-03 | ||
| EP11183692 | 2011-10-03 | ||
| EP11183679 | 2011-10-03 | ||
| EP11183681 | 2011-10-03 | ||
| US201161543611P | 2011-10-05 | 2011-10-05 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| EA201591204A2 EA201591204A2 (ru) | 2016-01-29 |
| EA201591204A3 EA201591204A3 (ru) | 2016-02-29 |
| EA030586B1 true EA030586B1 (ru) | 2018-08-31 |
Family
ID=48043185
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201591204A EA030586B1 (ru) | 2011-10-03 | 2012-10-03 | Интермедиат для получения антагонистов рецептора нейрокинина-3 |
| EA201490579A EA029340B1 (ru) | 2011-10-03 | 2012-10-03 | ХИРАЛЬНЫЕ N-АЦИЛ-5,6,7,(8-ЗАМЕЩЕННЫЕ)-ТЕТРАГИДРО[1,2,4]ТРИАЗОЛО[4,3-a]ПИРАЗИНЫ КАК СЕЛЕКТИВНЫЕ АНТАГОНИСТЫ РЕЦЕПТОРА NK-3, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ПРИМЕНЕНИЯ ПРИ НАРУШЕНИЯХ, ОПОСРЕДОВАННЫХ NK-3 РЕЦЕПТОРАМИ, И ИХ ХИРАЛЬНЫЙ СИНТЕЗ |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201490579A EA029340B1 (ru) | 2011-10-03 | 2012-10-03 | ХИРАЛЬНЫЕ N-АЦИЛ-5,6,7,(8-ЗАМЕЩЕННЫЕ)-ТЕТРАГИДРО[1,2,4]ТРИАЗОЛО[4,3-a]ПИРАЗИНЫ КАК СЕЛЕКТИВНЫЕ АНТАГОНИСТЫ РЕЦЕПТОРА NK-3, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ПРИМЕНЕНИЯ ПРИ НАРУШЕНИЯХ, ОПОСРЕДОВАННЫХ NK-3 РЕЦЕПТОРАМИ, И ИХ ХИРАЛЬНЫЙ СИНТЕЗ |
Country Status (20)
| Country | Link |
|---|---|
| US (4) | US9475814B2 (pl) |
| EP (2) | EP3029042A1 (pl) |
| JP (2) | JP6023814B2 (pl) |
| KR (1) | KR102049534B1 (pl) |
| CN (2) | CN103906750B9 (pl) |
| AU (1) | AU2012320568C1 (pl) |
| BR (1) | BR112014007652B1 (pl) |
| CA (1) | CA2849751C (pl) |
| CY (1) | CY1117773T1 (pl) |
| DK (1) | DK2763992T3 (pl) |
| EA (2) | EA030586B1 (pl) |
| ES (1) | ES2572604T3 (pl) |
| HR (1) | HRP20160396T1 (pl) |
| HU (1) | HUE028858T2 (pl) |
| MX (1) | MX367774B (pl) |
| PL (1) | PL2763992T3 (pl) |
| RS (1) | RS54833B1 (pl) |
| SI (1) | SI2763992T1 (pl) |
| SM (1) | SMT201600164B (pl) |
| WO (1) | WO2013050424A1 (pl) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX342161B (es) | 2010-04-02 | 2016-09-19 | Euroscreen Sa | Compuestos antagonistas selectivos de receptor nk-3 novedosos, composicion farmaceutica y metodos para utilizarse en trastornos transmitidos por receptores nk-3. |
| US10065960B2 (en) | 2010-04-02 | 2018-09-04 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| CN103906750B9 (zh) | 2011-10-03 | 2016-10-12 | 欧洲筛选有限公司 | 作为选择性NK-3受体拮抗剂的新型手性N-酰基-5,6,7,(8-取代的)-四氢-[1，2,4]三唑并[4，3-a]吡嗪、药物组合物、用于NK-3受体介导的疾病中的方法及其手性合成 |
| US10183948B2 (en) | 2013-03-29 | 2019-01-22 | Ogeda Sa | N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists |
| CA2907813C (en) | 2013-03-29 | 2021-09-07 | Euroscreen Sa | Novel n-acyl-(3-substituted)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor-mediated disorders |
| CA2907814C (en) | 2013-03-29 | 2021-07-13 | Euroscreen Sa | Novel n-acyl-(3-substituted)-(8-methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor-mediated disorders |
| ES2646488T3 (es) | 2013-03-29 | 2017-12-14 | Ogeda S.A. | N-acil-(3-sustituido)-(8-sustituido)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazinas como antagonistas selectivos del receptor NK-3, composición farmacéutica, métodos para uso en trastornos mediados por el receptor NK-3 |
| GB201315846D0 (en) | 2013-09-05 | 2013-10-23 | Imp Innovations Ltd | Method for treating or preventing hot flushes |
| MX367633B (es) * | 2014-09-25 | 2019-08-29 | Ogeda S A | Nueva sintesis quiral de n-acil-(3-sustituidas)-(8-sustituidas)-5, 6-dihidro-[1,2,4]triazolo[4,3-a]pirazinas. |
| EP3271015B8 (en) * | 2015-03-16 | 2023-11-01 | Ogeda N.V. | Nk-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat |
| JP2021014404A (ja) * | 2017-10-13 | 2021-02-12 | アステラス製薬株式会社 | トリアゾロピラジン誘導体の塩及び結晶 |
| CN113164459B (zh) | 2018-09-28 | 2024-09-03 | 詹森药业有限公司 | 单酰基甘油脂肪酶调节剂 |
| WO2020128003A1 (en) * | 2018-12-21 | 2020-06-25 | Ogeda Sa | SYNTHESIS OF 3-METHYL-1,2,4-THIADIAZOLE-5-CARBOHYDRAZIDE OR OF THE METHYL-d3 DEUTERATED FORM THEREOF |
| CN111499640A (zh) * | 2019-01-31 | 2020-08-07 | 上海医药工业研究院 | 哌嗪并三唑类衍生物的手性拆分方法 |
| WO2020211798A1 (zh) * | 2019-04-16 | 2020-10-22 | 上海翰森生物医药科技有限公司 | 含二并环类衍生物抑制剂、其制备方法和应用 |
| ES3037365T3 (en) * | 2019-09-30 | 2025-10-01 | Janssen Pharmaceutica Nv | Radiolabelled mgl pet ligands |
| CN113527307B (zh) * | 2020-04-20 | 2024-10-11 | 上海翰森生物医药科技有限公司 | 含三唑基的并环类衍生物抑制剂、其制备方法和应用 |
| CN113549074A (zh) * | 2020-04-26 | 2021-10-26 | 上海翰森生物医药科技有限公司 | 含三唑基的并环类衍生物抑制剂、其制备方法和应用 |
| CA3186086A1 (en) * | 2020-07-30 | 2022-02-03 | Yidong Su | Nitrogen-containing fused ring derivative inhibitor, preparation method therefor and use thereof |
| WO2022222963A1 (zh) * | 2021-04-21 | 2022-10-27 | 长春金赛药业有限责任公司 | 含咪唑稠环类衍生物、其制备方法及其在医药上的应用 |
| CN120787232A (zh) * | 2023-03-10 | 2025-10-14 | 山东绿叶制药有限公司 | Nk-3受体拮抗剂化合物、药物组合物、其制备方法和应用 |
| CN121358715A (zh) * | 2023-07-03 | 2026-01-16 | Ａｇｃ株式会社 | 3-甲基-1,2,4-噻二唑-5-碳酰肼的新型制造方法 |
| CN121358716A (zh) * | 2023-07-03 | 2026-01-16 | Ａｇｃ株式会社 | 3-甲基-1,2,4-噻二唑-5-碳酰肼的新型制造方法 |
| EP4628491A1 (en) | 2024-04-05 | 2025-10-08 | Química Sintética, S.A. | Synthesis of intermediates for the preparation of neurokinin-3 receptor antagonists |
| CN118290429B (zh) * | 2024-06-06 | 2024-10-11 | 山东百诺医药股份有限公司 | 非唑奈坦中间体及非唑奈坦的制备方法 |
| CN118878478B (zh) * | 2024-07-11 | 2025-10-14 | 深圳市华先医药科技有限公司 | 一种构建非唑奈坦手性片段的路线及其中间体和制备方法 |
| CN118955563B (zh) * | 2024-10-16 | 2025-02-11 | 上海翰森生物医药科技有限公司 | 一种含氮并环类衍生物的制备方法 |
| CN119775279B (zh) * | 2024-12-20 | 2025-12-30 | 上海皓元医药股份有限公司 | 一种利用手性辅基合成非唑奈坦及其中间体的方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998014433A1 (en) * | 1996-09-30 | 1998-04-09 | Pfizer Inc. | Aralkyl and aralkylidene heterocyclic lactams and imides |
| WO2003017939A2 (en) * | 2001-08-24 | 2003-03-06 | Yale University | Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment |
| WO2004089915A1 (en) * | 2003-04-10 | 2004-10-21 | Warner-Lambert Company Llc | Piperazine derivative renin inhibitors |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3252483B2 (ja) | 1992-10-20 | 2002-02-04 | 東レ株式会社 | ３環性トリアゾロ誘導体の製造方法 |
| EP0726260A1 (en) | 1995-02-08 | 1996-08-14 | American Cyanamid Company | Herbicidal (1,2,4)thiadiazoles |
| EP1146873B1 (en) | 1999-01-25 | 2005-03-16 | Smithkline Beecham Corporation | Anti-androgens and methods for treating disease |
| KR20020005653A (ko) * | 1999-04-01 | 2002-01-17 | 실버스타인 아써 에이. | 소르비톨 디하이드로게나제 저해제로서의 아미노피리미딘 |
| US7307164B2 (en) * | 2002-03-25 | 2007-12-11 | Merck & Co., Inc. | β-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| DK1537114T3 (da) | 2002-08-07 | 2006-11-13 | Novartis Ag | Organiske forbindelser som midler til behandling af aldosteronmedierede tilstande |
| MY139563A (en) | 2002-09-04 | 2009-10-30 | Bristol Myers Squibb Co | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
| AR043443A1 (es) | 2003-03-07 | 2005-07-27 | Merck & Co Inc | Procedimiento de preparacion de tetrahidrotriazolopirazinas y productos intermedios |
| CA2540061A1 (en) | 2003-09-30 | 2005-04-14 | Merck & Co., Inc. | Phenyl pyrrolidine ether tachykinin receptor antagonists |
| EP1716152B1 (en) * | 2004-02-18 | 2008-07-30 | AstraZeneca AB | Fused hetrocyclic compounds and their use as metabotropic receptor antagonists for the treatment of gastrointestinal disorders |
| GB0509405D0 (en) * | 2005-05-10 | 2005-06-15 | Merck Sharp & Dohme | Therapeutic compounds |
| EP1976527A4 (en) * | 2006-01-11 | 2009-04-22 | Merck & Co Inc | CONDENSED TRIAZOL TACHYKININE RECEPTOR ANTAGONISTS |
| TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
| GB0610680D0 (en) | 2006-05-31 | 2006-07-12 | Istituto Di Ricerche D Biolog | Therapeutic compounds |
| US7943617B2 (en) | 2006-11-27 | 2011-05-17 | Bristol-Myers Squibb Company | Heterobicyclic compounds useful as kinase inhibitors |
| EA201000046A1 (ru) | 2007-06-21 | 2011-02-28 | Кара Терапеутикс, Инк. | Замещенные имидазогетероциклы |
| ATE537175T1 (de) | 2007-10-19 | 2011-12-15 | Boehringer Ingelheim Int | Neue piperazino-dihydrothienopyrimidin-derivate |
| ES2525237T3 (es) | 2007-11-29 | 2014-12-19 | Boehringer Ingelheim International Gmbh | Derivados de amidas del ácido 6,7-dihidro-5H-imidazo[1,2-a]imidazol-3-carboxílico |
| TW200930713A (en) * | 2007-12-03 | 2009-07-16 | Takeda Pharmaceutical | Nitrogen-containing heterocyclic compound and use thereof |
| CA2711782C (en) * | 2008-01-09 | 2017-01-03 | Array Biopharma Inc. | 5h-cyclopenta[d]pyrimidines as akt protein kinase inhibitors |
| JP2011509962A (ja) | 2008-01-17 | 2011-03-31 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 置換スルホンアミド誘導体 |
| EP2090576A1 (en) * | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
| EP2085398A1 (en) | 2008-02-01 | 2009-08-05 | Merz Pharma GmbH & Co. KGaA | Pyrazolopyrimidines, a process for their preparation and their use as medicine |
| JP5654001B2 (ja) | 2009-04-29 | 2015-01-14 | グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ | Ｐ２Ｘ７調節因子としての５，６，７，８−テトラヒドロ［１，２，４］トリアゾロ［４，３−ａ］ピラジン誘導体 |
| GB0907515D0 (en) | 2009-04-30 | 2009-06-10 | Glaxo Group Ltd | Compounds |
| JPWO2011007756A1 (ja) | 2009-07-13 | 2012-12-27 | 武田薬品工業株式会社 | 複素環化合物及びその用途 |
| US10065960B2 (en) | 2010-04-02 | 2018-09-04 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| MX342161B (es) | 2010-04-02 | 2016-09-19 | Euroscreen Sa | Compuestos antagonistas selectivos de receptor nk-3 novedosos, composicion farmaceutica y metodos para utilizarse en trastornos transmitidos por receptores nk-3. |
| CN103906750B9 (zh) | 2011-10-03 | 2016-10-12 | 欧洲筛选有限公司 | 作为选择性NK-3受体拮抗剂的新型手性N-酰基-5,6,7,(8-取代的)-四氢-[1，2,4]三唑并[4，3-a]吡嗪、药物组合物、用于NK-3受体介导的疾病中的方法及其手性合成 |
| CA2907814C (en) | 2013-03-29 | 2021-07-13 | Euroscreen Sa | Novel n-acyl-(3-substituted)-(8-methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor-mediated disorders |
| ES2646488T3 (es) | 2013-03-29 | 2017-12-14 | Ogeda S.A. | N-acil-(3-sustituido)-(8-sustituido)-5,6-dihidro-[1,2,4]triazolo[4,3-a]pirazinas como antagonistas selectivos del receptor NK-3, composición farmacéutica, métodos para uso en trastornos mediados por el receptor NK-3 |
| CA2907813C (en) | 2013-03-29 | 2021-09-07 | Euroscreen Sa | Novel n-acyl-(3-substituted)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor-mediated disorders |
| MX367633B (es) | 2014-09-25 | 2019-08-29 | Ogeda S A | Nueva sintesis quiral de n-acil-(3-sustituidas)-(8-sustituidas)-5, 6-dihidro-[1,2,4]triazolo[4,3-a]pirazinas. |
-
2012
- 2012-10-03 CN CN201280048708.3A patent/CN103906750B9/zh active Active
- 2012-10-03 JP JP2014533873A patent/JP6023814B2/ja active Active
- 2012-10-03 KR KR1020147012169A patent/KR102049534B1/ko active Active
- 2012-10-03 SI SI201230520A patent/SI2763992T1/sl unknown
- 2012-10-03 ES ES12766991.9T patent/ES2572604T3/es active Active
- 2012-10-03 AU AU2012320568A patent/AU2012320568C1/en active Active
- 2012-10-03 WO PCT/EP2012/069546 patent/WO2013050424A1/en not_active Ceased
- 2012-10-03 CN CN201510557452.4A patent/CN105175421B/zh active Active
- 2012-10-03 BR BR112014007652-9A patent/BR112014007652B1/pt active IP Right Grant
- 2012-10-03 EA EA201591204A patent/EA030586B1/ru not_active IP Right Cessation
- 2012-10-03 RS RS20160334A patent/RS54833B1/sr unknown
- 2012-10-03 EA EA201490579A patent/EA029340B1/ru not_active IP Right Cessation
- 2012-10-03 CA CA2849751A patent/CA2849751C/en active Active
- 2012-10-03 EP EP15201386.8A patent/EP3029042A1/en not_active Withdrawn
- 2012-10-03 US US14/349,595 patent/US9475814B2/en active Active
- 2012-10-03 HR HRP20160396TT patent/HRP20160396T1/hr unknown
- 2012-10-03 DK DK12766991.9T patent/DK2763992T3/en active
- 2012-10-03 EP EP12766991.9A patent/EP2763992B9/en active Active
- 2012-10-03 MX MX2014004057A patent/MX367774B/es active IP Right Grant
- 2012-10-03 PL PL12766991T patent/PL2763992T3/pl unknown
- 2012-10-03 HU HUE12766991A patent/HUE028858T2/hu unknown
-
2016
- 2016-05-17 CY CY20161100426T patent/CY1117773T1/el unknown
- 2016-06-09 SM SM201600164T patent/SMT201600164B/it unknown
- 2016-07-28 JP JP2016148578A patent/JP6294918B2/ja active Active
- 2016-09-08 US US15/259,922 patent/US10065961B2/en active Active
-
2018
- 2018-07-27 US US16/047,740 patent/US10683295B2/en active Active
-
2020
- 2020-05-21 US US16/880,337 patent/US10941151B2/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998014433A1 (en) * | 1996-09-30 | 1998-04-09 | Pfizer Inc. | Aralkyl and aralkylidene heterocyclic lactams and imides |
| WO2003017939A2 (en) * | 2001-08-24 | 2003-03-06 | Yale University | Piperazinone compounds as anti-tumor and anti-cancer agents and methods of treatment |
| WO2004089915A1 (en) * | 2003-04-10 | 2004-10-21 | Warner-Lambert Company Llc | Piperazine derivative renin inhibitors |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EA030586B1 (ru) | Интермедиат для получения антагонистов рецептора нейрокинина-3 | |
| JP7257387B2 (ja) | スピロ環化合物並びにその作製及び使用方法 | |
| KR20220042206A (ko) | Rip1 억제 화합물 및 그를 제조 및 사용하는 방법 | |
| KR20220079919A (ko) | 헤테로시클릭 rip1 억제 화합물 | |
| KR20230033712A (ko) | Rip1k 억제제 | |
| KR102217206B1 (ko) | 선택적 NK-3 수용체 길항제로서의 신규한 키랄 N-아실-5,6,7,(8-치환된)-테트라히드로-[1,2,4]트리아졸로[4,3-a]피라진, 의약 조성물, NK-3 수용체 매개 질환에 사용하는 방법 및 그의 키랄 합성법 | |
| HK1197676B (en) | Novel chiral n-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, and methods for use in nk-3 receptor mediated disorders | |
| HK40032869B (en) | Spirocycle compounds and methods of making and using same | |
| HK40032869A (en) | Spirocycle compounds and methods of making and using same | |
| HK1243063B (zh) | 作为詹纳斯相关激酶(jak)抑制剂的吡咯并[2，3-d]嘧啶衍生物 | |
| HK1213881B (en) | Pyrrolo [2, 3-d] pyrimidine derivatives as inhibitors of janus-related kinases (jak) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG TJ TM |